EP3326630A2 - Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie - Google Patents

Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie Download PDF

Info

Publication number
EP3326630A2
EP3326630A2 EP17191332.0A EP17191332A EP3326630A2 EP 3326630 A2 EP3326630 A2 EP 3326630A2 EP 17191332 A EP17191332 A EP 17191332A EP 3326630 A2 EP3326630 A2 EP 3326630A2
Authority
EP
European Patent Office
Prior art keywords
variations
rapamycin
derivative
composition
paclitaxel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17191332.0A
Other languages
English (en)
French (fr)
Other versions
EP3326630A3 (de
Inventor
Neil P. Desai
Patrick Soon-Shiong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abraxis Bioscience LLC
Original Assignee
Abraxis Bioscience LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abraxis Bioscience LLC filed Critical Abraxis Bioscience LLC
Publication of EP3326630A2 publication Critical patent/EP3326630A2/de
Publication of EP3326630A3 publication Critical patent/EP3326630A3/de
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention further provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise a taxane or a derivative thereof and a carrier protein (e.g ., albumin) in combination with one or more other therapeutic agents and/or therapies.
  • a carrier protein e.g ., albumin
  • the present invention provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise paclitaxel and an albumin in combination with one or more other therapeutic agents and/or therapies.
  • the other therapeutic agent is rapamycin or a derivative thereof.
  • the amount of the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof in the effective amount of the composition is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg. In some variations, rapamycin or derivative thereof or a taxane ( e.g ., paclitaxel) or a derivative thereof in the effective amount of the composition is about 5 to about 300 mg/m 2 .
  • rapamycin or derivative thereof or a taxane (e.g ., paclitaxel) or a derivative thereof in the effective amount of the composition is about 30 to about 100 mg/m 2 .
  • the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof is administered parenterally ( e.g ., intravenously).
  • the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof is administered by inhalation.
  • the amount of the rapamycin or derivatives thereof or the taxane (e.g. , paclitaxel) or a derivative thereof in the composition is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
  • the carrier is suitable for parenteral administration ( e.g ., intravenously). In some variations, the carrier is suitable for administration by inhalation.
  • the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof is the only pharmaceutically active agent for the treatment of pulmonary hypertension that is contained in the composition.
  • the composition comprises rapamycin. In some variations, the composition comprises paclitaxel. In some variations, the composition comprises both rapamycin and paclitaxel. In some variations, the composition comprises more than about 50% of the rapamycin or derivative thereof or the taxane ( e.g ., paclitaxel) or a derivative thereof in nanoparticle form.
  • the carrier protein is albumin, such as human serum albumin. In some variations, the average diameter of the nanoparticles in the composition is no greater than about 200 nm. In some variations, the weight ratio of the carrier protein to the rapamycin or derivative thereof or the taxane ( e.g ., paclitaxel) or a derivative thereof in the nanoparticles is less than about 18:1.
  • the PAH is associated with persistent pulmonary hypertension of a newborn. In some variations, the PAH is associated with pulmonary veno-occusive disease. In some variations, the PAH is associated with pulmonary capillary hemangiomatosis. In some variations, the pulmonary hypertension is pulmonary venous hypertension. In some variations, the pulmonary hypertension is pulmonary hypertension associated with disorders of the respiratory system and/or hypoxia. In some variations, the pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and/or embolic disease. In some variations, the pulmonary hypertension is miscellaneous pulmonary hypertension.
  • the miscellaneous pulmonary hypertension is associated with sarcoidosis, eosiniphilic granuloma, histicytosis X, lymphangiolomyiomatosis, or compression of pulmonary vessels (e.g ., adenopath, tumor, or fibrosing medianstinitis).
  • the pulmonary hypertension is associated with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the pulmonary hypertension is associated with pulmonary fibrosis.
  • the pulmonary hypertension is early stage pulmonary hypertension or advanced pulmonary hypertension.
  • one or more symptoms of the pulmonary hypertension are ameliorated.
  • the pulmonary hypertension is delayed or prevented.
  • the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof is the only pharmaceutically active agent for the treatment of pulmonary hypertension that is contained in the kit.
  • the kit comprises rapamycin.
  • the kit comprises paclitaxel.
  • the kit comprises both rapamycin and paclitaxel.
  • the composition comprises more than about 50% of the rapamycin or derivative thereof or the taxane (e.g ., paclitaxel) or a derivative thereof in nanoparticle form.
  • the carrier protein is albumin, such as human serum albumin.
  • the nanoparticle formulation of albumin and rapamycin and the nanoparticles formulation of albumin and a taxane enhances tissue penetration through albumin receptor (gp60)-mediated binding of the SPARC protein.
  • This increased specificity of Nab -rapamycin and Nab -paclitaxel may increase the effectiveness of rapamycin and a taxane (e.g ., paclitaxel) and may allow lower doses of rapamycin and a taxane ( e.g., paclitaxel) to be used, which would minimize toxic effects from rapamycin and a taxane ( e.g ., paclitaxel) while still inhibiting, stabilizing, preventing, or delaying pulmonary hypertension.
  • a taxane e.g ., paclitaxel
  • compositions includes and is applicable to compositions of the invention.
  • compositions includes and is applicable to compositions of the invention.
  • invention also provides pharmaceutical compositions comprising the components described herein.
  • Taxanes include, but are not limited to, compounds that are structurally similar to or are in the same general chemical class such as paclitaxel (i.e., taxol), docetaxel ( i.e., taxotere), or ortataxel, and pharmaceutically acceptable salts, derivatives, or analogs of paclitaxel, docetaxel, and ortataxel.
  • paclitaxel i.e., taxol
  • docetaxel i.e., taxotere
  • or ortataxel or pharmaceutically acceptable salts, derivatives, or analogs of paclitaxel, docetaxel, and ortataxel.
  • rapamycin or a derivative thereof increases basal AKT activity, increases AKT phosphorylation, increases PI3-kinase activity, increases the length of activation of AKT (e.g ., activation induced by exogenous IGF-1), inhibits serine phosphorylation of IRS-1, inhibits IRS-1 degradation, inhibits or alters CXCR4 subcellular localization, inhibits VEGF secretion, decreases expression of cyclin D2, decreases expression of survivin, inhibits IL-6-induced multiple myeloma cell growth, inhibits pulmonary hypertension cell proliferation, increases apoptosis, increases cell cycle arrest, increases cleavage of poly(ADPribose) polymerase, increases cleavage of caspase-8/caspase-9, alters or inhibits signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and/or cyclin Dl/retinoblastoma pathways, inhibits angiogenesis,
  • the derivative of rapamycin retains one or more similar biological, pharmacological, chemical and/or physical properties (including, for example, functionality) as rapamycin.
  • An exemplary rapamycin derivative includes benzoyl rapamycin, such as that disclosed in paragraph [0022] of WO 2006/089207 , which is hereby incorporated by reference in its entirety.
  • rapamycin derivatives include WY-090217, AY-22989, NSC-226080, SiiA-9268A, oxaazacyclohentriacontine, temsirolimus (CCI 779 (Wyeth)), everolimus (RAD 001 (Novartis)), pimecrolimus (ASM981), SDZ-RAD, SAR943, ABT-578, AP23573, and Biolimus A9.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g ., preventing or delaying the worsening of the disease), preventing or delaying the occurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, decreasing the dose of one or more other medications required to treat the disease, increasing the quality of life, and/or prolonging survival.
  • the composition reduces the severity of one or more symptoms associated with pulmonary hypertension by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the composition.
  • treatment is a reduction of pathological consequence of pulmonary hypertension. The methods of the invention contemplate any one or more of these aspects of treatment.
  • “delaying" the development of pulmonary hypertension means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that "delays" development of pulmonary hypertension is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Pulmonary hypertension development can be detectable using standard methods, such as routine physical exams, x-ray, electrocardiogram, and echocardiogram. Development may also refer to disease progression that may be initially undetectable and includes occurrence and onset.
  • an "at risk” individual is an individual who is at risk of developing pulmonary hypertension.
  • An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of pulmonary hypertension, which are described herein. An individual having one or more of these risk factors has a higher probability of developing pulmonary hypertension than an individual without these risk factor(s).
  • pharmaceutically active compound a chemical compound that induces a desired effect, e.g ., treating, stabilizing, preventing, and/or delaying pulmonary hypertension.
  • combination therapy is meant a first therapy that includes nanoparticles comprising rapamycin or a derivative thereof and a carrier protein and/or nanoparticles comprising a taxane (e.g . paclitaxel) or a derivative thereof and a carrier protein in conjunction with a second therapy (e.g ., surgery or a therapeutic agent) useful for treating, stabilizing, preventing, and/or delaying pulmonary hypertension.
  • a second therapy e.g ., surgery or a therapeutic agent
  • Administration in "conjunction with” another compound includes administration in the same or different composition(s), either sequentially, simultaneously, or continuously.
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • an "effective amount” may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a nanoparticle composition (e.g ., a composition including rapamycin and a carrier protein and/or a composition including a taxane ( e.g ., paclitaxel) and a carrier protein) may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • a nanoparticle composition e.g ., a composition including rapamycin and a carrier protein and/or a composition including a taxane (e.g ., paclitaxel) and a carrier protein
  • a “therapeutically effective amount” refers to an amount of a composition (e.g ., nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein or nanoparticles that comprise a taxane ( e.g ., paclitaxel) or a derivative thereof and a carrier protein), a therapy, or a combination therapy sufficient to produce a desired therapeutic outcome (e.g ., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of pulmonary hypertension).
  • a composition e.g ., nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein or nanoparticles that comprise a taxane (e.g ., paclitaxel) or a derivative thereof and a carrier protein
  • a therapy e.g ., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of pulmonary hypertension.
  • a “prophylactically effective amount” refers to an amount of a composition (e.g ., nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein and/or nanoparticles that comprise a taxane (e.g., paclitaxel) or a derivative thereof and a carrier protein), a therapy, or a combination therapy sufficient to prevent or reduce the severity of one or more future symptoms of pulmonary hypertension when administered to an individual who is susceptible and/or who may develop pulmonary hypertension.
  • a composition e.g ., nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein and/or nanoparticles that comprise a taxane (e.g., paclitaxel) or a derivative thereof and a carrier protein
  • a therapy e.g., paclitaxel
  • beneficial or desired results include, e.g ., results such as eliminating or reducing the risk, lessening the severity of future disease, or delaying the onset of the disease (e.g ., delaying biochemical, histologic and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during future development of the disease).
  • proteins refers to polypeptides or polymers of amino acids of any length (including full length or fragments), which may be linear or branched, comprise modified amino acids, and/or be interrupted by non-amino acids.
  • the term also encompasses an amino acid polymer that has been modified naturally or by intervention, including, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within this term are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art.
  • the proteins described herein may be naturally-occurring, i.e., obtained or derived from a natural source (e.g ., blood) or synthesized (e.g ., chemically synthesized or by synthesized by recombinant DNA techniques). Exemplary carrier proteins are described herein.
  • antimicrobial agent refers to an agent that is capable of inhibiting (e.g ., delaying, reducing, slowing, and/or preventing) the growth of one or more microorganisms.
  • Significant microbial growth can be measured or indicated by a number of ways known in the art, such as one or more of the following: (i) microbial growth in a composition that is enough to cause one or more adverse effects to an individual when the composition is administered to the individual; (ii) more than about 10-fold increase in microbial growth over a certain period of time (for example over a 24 hour period) upon extrinsic contamination (e.g., exposure to 10-103 colony forming units at a temperature in the range of 20 to 25 °C).
  • Other indicia of significant microbial growth are described in U.S.S.N. 11/514,030, filed 8/30/2006 , which is hereby incorporated by reference in its entirety.
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g ., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • references to "about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.'
  • the invention provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising rapamycin or a derivative thereof and a carrier protein (e.g ., albumin).
  • a carrier protein e.g ., albumin
  • the present invention provides a method of treating pulmonary hypertension in an individual ( e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising rapamycin and an albumin.
  • the invention also provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane or a derivative thereof and a carrier protein (e.g ., albumin).
  • a composition comprising nanoparticles comprising a taxane or a derivative thereof and a carrier protein (e.g ., albumin).
  • the present invention provides a method of treating pulmonary hypertension in an individual ( e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin.
  • the invention also provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g. , albumin) in combination with one or more other therapeutic agents and/or therapies.
  • a carrier protein e.g. , albumin
  • the present invention provides a method of treating pulmonary hypertension in an individual ( e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise rapamycin and an albumin in combination with one or more other therapeutic agents and/or therapies.
  • the other therapeutic agent is a taxane or a derivative thereof.
  • the invention also provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition comprising nanoparticles that comprise a taxane or a derivative thereof and a carrier protein (e.g ., albumin) in combination with one or more other therapeutic agents and/or therapies.
  • a composition comprising nanoparticles that comprise a taxane or a derivative thereof and a carrier protein (e.g ., albumin) in combination with one or more other therapeutic agents and/or therapies.
  • the present invention provides a method of treating pulmonary hypertension in an individual (e.g ., human) comprising administering to the individual an effective amount of a composition that comprise nanoparticles comprising paclitaxel and an albumin in combination with one or more other therapeutic agents and/or therapies.
  • the other therapeutic agent is rapamycin or a derivative thereof.
  • the rapamycin or a derivative thereof is a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin). In some variations, the rapamycin or derivative thereof is rapamycin. In some variations, the rapamycin is a composition comprising nanoparticles that comprise rapamycin and albumin.
  • the pulmonary hypertension is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • PAH is idiopathic PAH (formally primary pulmonary hypertension).
  • PAH is sporadic PAH (SPAH).
  • SPAH is associated with a mutation in the gene bone morphogenetic protein receptor 2 (BMPR2).
  • BMPR2 the gene bone morphogenetic protein receptor 2
  • FPAH familial PAH
  • FPAH is associated with a mutation in a gene in the TGF- ⁇ pathway.
  • FPAH is associated with a mutation in the gene bone morphogenetic protein receptor 2 (BMPR2).
  • FPAH is associated with a mutation in ALK-1.
  • the APAH is associated with collagen vascular disease (e.g ., scleroderma or lupus), congenital heart disease, congenital systemic-to-pulmonary shunts, portal hypertension, chronic liver disease, human immunodeficiency virus, drugs and toxins (e.g., diet drugs ( e.g., fenfluramine or dexfenfluramine), cocaine, or methamphetamine), hemorrhagic hereditary telangectasis, glycogen storage disease, thyroid disorders, Gaucher's disease, haemoglobinopathies, myeloproliferative disorders, or splenectomy.
  • collagen vascular disease e.g scleroderma or lupus
  • congenital heart disease e.g., congenital heart disease, congenital systemic-to-pulmonary shunts, portal hypertension, chronic liver disease, human immunodeficiency virus, drugs and toxins (e.g., diet drugs ( e.g
  • the PAH is associated with persistent pulmonary hypertension of a newborn. In some variations, the PAH is associated with significant venous or capillary involvement. In some variations, the PAH is associated with pulmonary veno-occusive disease (i.e., PVOD). In some variations, the PAH is associated with pulmonary capillary hemangiomatosis ( i . e ., PCH).
  • the PH is PH associated with left heart disease.
  • the PH associated with left heart disease is PH associated with left sided atrial or ventricular heart disease.
  • the PH associated with left heart disease is left sided valvular heart disease.
  • the PH is PH due to chronic thrombotic and/or embolic disease.
  • the PH due to chronic thrombotic and/or embolic disease is thromboembolic obstruction of proximal pulmonary arteries, thromboembolic obstruction of distal pulmonary arteries, or non-thrombotic pulmonary embolism.
  • the PH is miscellaneous PH.
  • the miscellaneous PH is associated with sarcoidosis, eosiniphilic granuloma, histicytosis X, lymphangiolomyiomatosis, pulmonary Langerhans cell histiocytosis, or compression of pulmonary vessels ( e.g ., adenopath, tumor, or fibrosing medianstinitis).
  • the PH is associated with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the PH is associated with pulmonary fibrosis.
  • the PH is pulmonary venous hypertension.
  • the PAH is class 1, class 2, class 3, or class 4 PH according to the NYHA/WHO classification of functional status of patients with pulmonary hypertension.
  • class 1 PAH is characterized by, but not limited to, pulmonary hypertension but without resulting limitation of physical activity, such that ordinary physical activity does not cause dyspnoea or fatigue, chest pain or near syncope.
  • class 2 PAH is characterized by, but not limited to, pulmonary hypertension resulting in slight limitation of physical activity, such that patients are comfortable at rest and ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope.
  • class 3 PAH is characterized by, but not limited to, pulmonary hypertension resulting in marked limitation of physical activity, such that patients are comfortable at rest and less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope.
  • class 4 PAH is characterized by, but not limited to, pulmonary hypertension with inability to carry out any physical activity without symptoms, such that patients manifest signs of right heart failure, dyspnoea and/or fatigue may even be present at rest, and discomfort is increased by any physical activity.
  • the individual may be NYHA class II or IV despite three months of stable therapy (e.g ., prostacylin, phosphodiesterase type 5 inhibitor (sildenafil), endothelin receptor antagonist (ambrisenten), or combinations thereof).
  • stable therapy e.g ., prostacylin, phosphodiesterase type 5 inhibitor (sildenafil), endothelin receptor antagonist (ambrisenten), or combinations thereof.
  • angiogenesis in the pulmonary artery is inhibited and/or reduced by suppression of production of matrix metalloproteinases.
  • the methods of treatment provided herein inhibit and/or reduce inflammation in the pulmonary artery.
  • inflammation is inhibited and/or reduced by effecting neutrophil and T cell function.
  • the methods of treatment provided herein are effective in reducing symptoms of pulmonary hypertension in an animal model system where pulmonary hypertension is induced by either chronic hypoxia or monocrotaline.
  • the individual may have advanced disease or a lesser extent of disease.
  • the individual is at an early stage of a pulmonary hypertension.
  • the individual is at an advanced stage of pulmonary hypertension.
  • the individual has severe pulmonary hypertension. In some variations, the individual does not tolerate the toxicities of paclitaxel at traditional chemotherapeutic doses or formulations. In some variations, the individual may have echocardiographic evidence of right ventricular dysfunction. In some variations, the individual may have a 6-Minute Walk Distance of less than or equal to 380m. In some of the variations, the methods of treatment provided herein, the individual may be a human who is genetically or otherwise predisposed (e.g., at risk) to developing pulmonary hypertension who has or has not been diagnosed with pulmonary hypertension, as described herein.
  • these risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (e.g ., hereditary) considerations, and environmental exposure.
  • the individuals at risk for pulmonary hypertension include, e.g ., those having relatives who have experienced this disease and those whose risk is determined by analysis of genetic or biochemical markers.
  • the invention provides methods of inhibiting abnormal cell proliferation in a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising rapamycin or a derivative thereof and a carrier protein (e.g ., albumin).
  • the invention also provides methods of inhibiting abnormal cell proliferation in a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising taxane or a derivative thereof and a carrier protein (e.g ., albumin).
  • the abnormal cell proliferation is abnormal cell proliferation of smooth muscle and endothelial cells.
  • the invention provides methods of inhibiting and/or reducing angiogenesis in the pulmonary artery of a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising rapamycin or a derivative thereof and a carrier protein ( e.g ., albumin).
  • the invention also provides methods of inhibiting and/or reducing angiogenesis in the pulmonary artery of a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising taxane or a derivative thereof and a carrier protein (e.g ., albumin).
  • angiogenesis in the pulmonary artery is inhibited and/or reduced by suppression of production of matrix metalloproteinases.
  • the invention provides methods of inhibiting and/or reducing inflammation in the pulmonary artery of a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising rapamycin or a derivative thereof and a carrier protein (e.g ., albumin).
  • the invention also provides methods of inhibiting and/or reducing inflammation in the pulmonary artery of a patient having pulmonary hypertension comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising taxane or a derivative thereof and a carrier protein (e.g ., albumin).
  • inflammation is inhibited and/or reduced by effecting neutrophil and T cell function.
  • any of the method of treatment provided herein may be used to treat an individual who has previously been treated.
  • the methods of treatment provided herein may be used to treat an individual who has not previously been treated.
  • a taxane or a derivative thereof is the only pharmaceutical active agent administered to the individual.
  • the methods of treatment provided herein, a rapamycin or a derivative thereof is the only pharmaceutical active agent administered to the individual.
  • the first and/or second therapies do comprise a SPARC polypeptide or anti-SPARC antibody ( i.e. , other than SPARC polypeptide or anti-SPARC antibody).
  • the first and/or second therapies do not comprise a SPARC polypeptide or anti-SPARC antibody ( i.e. , other than SPARC polypeptide or anti-SPARC antibody).
  • any of the methods of treatment provided herein may be used to treat, stabilize, prevent, and/or delay any type or stage of pulmonary hypertension.
  • the individual is at least about any of 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old.
  • one or more symptoms of the pulmonary hypertension are ameliorated or eliminated.
  • the pulmonary hypertension is delayed or prevented.
  • the individual is a human
  • the dose of the inventive composition administered to an individual may vary with the particular composition, the method of administration, and the particular stage of pulmonary hypertension being treated.
  • the amount should be sufficient to produce a desirable response, such as a therapeutic or prophylactic response against pulmonary hypertension.
  • the amount of the composition is a therapeutically effective amount. In some variations, that amount of the composition is a prophylactically effective amount.
  • the amount of rapamycin or a derivative thereof and/or paclitaxel or a derivative thereof in the composition is below the level that induces a toxicological effect (i.e., an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual.
  • the invention provides a method of treating pulmonary hypertension in an individual by administering to the individual (e.g ., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • the amount of rapamycin or a derivative thereof in the composition is included in any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • the amount of rapamycin or derivative thereof in the effective amount of the composition is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
  • the concentration of the rapamycin in the composition is dilute (about 0.1 mg/ml) or concentrated (about 100 mg/ml), including for example any of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5 mg/ml.
  • the concentration of the rapamycin is at least about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml.
  • Exemplary effective amounts of rapamycin or a derivative thereof in the nanoparticle composition include, but are not limited to, about any of 25 mg/m 2 , 30 mg/m 2 , 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 180 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 250 mg/m 2 , 260 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 500 mg/m 2 , 540 mg/m 2 , 750 mg/m 2 , 1000 mg/m 2 , or 1080 mg/m 2 rapamycin.
  • the composition includes less than about any of 350 mg/m 2 , 300 mg/m 2 , 250 mg/m 2 , 200 mg/m 2 , 150 mg/m 2 , 120 mg/m 2 , 100 mg/m 2 , 90 mg/m 2 , 50 mg/m 2 , or 30 mg/m 2 rapamycin or a derivative thereof.
  • the amount of the rapamycin or a derivative thereof per administration is less than about any of 25 mg/m 2 , 22 mg/m 2 , 20 mg/m 2 , 18 mg/m 2 , 15 mg/m 2 , 14 mg/m 2 , 13 mg/m 2 , 12 mg/m 2 , 11 mg/m 2 , 10 mg/m 2 , 9 mg/m 2 , 8 mg/m 2 , 7 mg/m 2 , 6 mg/m 2 , 5 mg/m 2 , 4 mg/m 2 , 3 mg/m 2 , 2 mg/m 2 , or 1 mg/m 2 .
  • the effective amount of rapamycin or a derivative thereof in the composition is included in any of the following ranges: about 1 to about 5 mg/m 2 , about 5 to about 10 mg/m 2 , about 10 to about 25 mg/m 2 , about 25 to about 50 mg/m 2 , about 50 to about 75 mg/m 2 , about 75 to about 100 mg/m 2 , about 100 to about 125 mg/m 2 , about 125 to about 150 mg/m 2 , about 150 to about 175 mg/m 2 , about 175 to about 200 mg/m 2 , about 200 to about 225 mg/m 2 , about 225 to about 250 mg/m 2 , about 250 to about 300 mg/m 2 , about 300 to about 350 mg/m 2 , or about 350 to about 400 mg/m 2 .
  • the effective amount of rapamycin or a derivative thereof in the composition includes at least about any of 1 mg/kg, 2.5 mg/kg, 3.5 mg/kg, 5 mg/kg, 6.5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg.
  • the effective amount of rapamycin or a derivative thereof in the composition includes less than about any of 350 mg/kg, 300 mg/kg, 250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg, 5 mg/kg, 3.5 mg/kg, 2.5 mg/kg, or 1 mg/kg rapamycin or a derivative thereof.
  • Exemplary dosing frequencies include, but are not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks.
  • the composition is administered about once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.
  • the composition is administered at least about any of 1x, 2x, 3x, 4x, 5x, 6x, or 7x ( i . e ., daily) a week.
  • the intervals between each administration are less than about any of 6 months, 3 months, 1 month, 20 days, 15, days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some variations, the intervals between each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some variations, there is no break in the dosing schedule. In some variations, the interval between each administration is no more than about a week.
  • the administration of the composition can be extended over an extended period of time, such as from about a month up to about seven years.
  • the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.
  • the rapamycin or derivative thereof is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the rapamycin or a derivative thereof at each administration is about 0.25 mg/m 2 to about 75 mg/m 2 , such as about 0.25 mg/m 2 to about 25 mg/m 2 or about 25 mg/m 2 to about 50 mg/m 2 .
  • the dosage of rapamycin in a nanoparticle composition can be in the range of 5-400 mg/m 2 when given on a 3 week schedule, or 5-250 mg/m 2 when given on a weekly schedule.
  • the amount of rapamycin is about 80 to about 180 mg/m 2 (e.g., about 100 mg/m 2 to about 150 mg/m 2 , such as about 120 mg/m 2 ).
  • exemplary dosing schedules for the administration of the nanoparticle composition include, but are not limited to, 100 mg/m 2 , weekly, without break; 30 mg/m 2 weekly, 3 out of four weeks; 60 mg/m 2 weekly, 3 out of four weeks; 75 mg/m 2 weekly, 3 out of four weeks; 80 mg/m 2 weekly, 3 out of four weeks; 100 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 2 out of 3 weeks; 130 mg/m 2 , weekly, without break; 175 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 3 weeks; 180-300 mg/m 2 , every three weeks; 60-175 mg/m 2 , weekly, without break; 20-150 mg/m 2 twice a week; and 150-250 mg/m 2 twice
  • the invention provides a method of treating pulmonary hypertension in an individual by parenterally administering to the individual (e.g ., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • the invention also provides a method of treating pulmonary hypertension in an individual by intravenous, intra-arterial, intramuscular, subcutaneous, inhalation, intraperitoneal, nasally, or intra-tracheal administering to the individual (e.g ., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous.
  • an effective amount of the composition is administered systemically (e.g ., intravenously) over a period of less than 30 minutes.
  • an effective amount of the composition is administered systemically (e.g ., intravenously) over a period of about any of 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute.
  • about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg, of the rapamycin or derivative thereof is administered per dose.
  • a taxane is not contained in the composition.
  • the rapamycin or derivative thereof is the only pharmaceutically active agent for the treatment of pulmonary hypertension that is contained in the composition.
  • the invention provides a method of treating pulmonary hypertension in an individual by administering to the individual (e.g ., a human) an effective amount of a composition comprising nanoparticles that comprise a taxane or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • a composition comprising nanoparticles that comprise a taxane or a derivative thereof and a carrier protein (e.g ., albumin such as human serum albumin).
  • the amount of a taxane (e.g ., paclitaxel) or a derivative thereof in the composition is included in any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • a taxane e.g ., paclitaxel
  • the amount of a taxane (e.g ., paclitaxel) or derivative thereof in the effective amount of the composition is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
  • the concentration of the taxane (e.g ., paclitaxel) in the composition is dilute (about 0.1 mg/ml) or concentrated (about 100 mg/ml), including example any of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5 mg/ml.
  • the concentration of the taxane is at least about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml.
  • the taxane e.g ., paclitaxel
  • Exemplary effective amounts of a taxane (e.g ., paclitaxel) or a derivative thereof in the nanoparticle composition include, but are not limited to, about any of 25 mg/m 2 , 30 mg/m 2 , 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 180 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 250 mg/m 2 , 260 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 500 mg/m 2 , 540 mg/m 2 , 750 mg/m 2 , 1000 mg/m 2 , or 1080 mg/m 2 of a taxane ( e.g ., paclitaxel).
  • a taxane
  • the composition includes less than about any of 350 mg/m 2 , 300 mg/m 2 , 250 mg/m 2 , 200 mg/m 2 , 150 mg/m 2 , 120 mg/m 2 , 100 mg/m 2 , 90 mg/m 2 , 50 mg/m 2 , or 30 mg/m 2 of a taxane (e.g ., paclitaxel) or a derivative thereof.
  • a taxane e.g ., paclitaxel
  • the amount of the taxane (e.g ., paclitaxel) or a derivative thereof per administration is less than about any of 25 mg/m 2 , 22 mg/m 2 , 20 mg/m 2 , 18 mg/m 2 , 15 mg/m 2 , 14 mg/m 2 , 13 mg/m 2 , 12 mg/m 2 , 11 mg/m 2 , 10 mg/m 2 , 9 mg/m 2 , 8 mg/m 2 , 7 mg/m 2 , 6 mg/m 2 , 5 mg/m 2 , 4 mg/m 2 , 3 mg/m 2 , 2 mg/m 2 , or 1 mg/m 2 .
  • the taxane e.g ., paclitaxel
  • HSA Human serum albumin
  • hydrophobic binding sites a total of eight for fatty acids, an endogenous ligand of HSA
  • binds a diverse set of drugs, especially neutral and negatively charged hydrophobic compounds Goodman et al., The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill New York (1996 )
  • Two high affinity binding sites have been proposed in subdomains IIA and IIIA of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface which function as attachment points for polar ligand features (see, e.g., Fehske et al., Biochem. Pharmcol., 30, 687-92 (1981 ), Vorum, Dan.
  • side effects are merely exemplary and other side effects, or combination of side effects, associated with rapamycin and/or a taxane (e.g ., paclitaxel) can be reduced.
  • the side effects may be immediate or delayed (such as not occurring for a few days, weeks, months, or years after treatment begins).
  • compositions of the invention include a sugar for use in the methods of treatment described herein.
  • compositions of the invention include both a sugar and an antimicrobial agent for use in the methods of treatment described herein.
  • Exemplary sugars and variations for the use of sugars are disclosed in U.S.S.N. 11/514,030, filed 8/30/2006 (such as those described in paragraphs [0084] to [0090]).
  • the sugar serves as a reconstitution enhancer which causes a lyophilized composition to dissolve or suspend in water and/or aqueous solution more quickly than the lyophilized composition would dissolve without the sugar.
  • the amount of rapamycin or a derivative thereof in the composition is included in any of the following ranges: about 5 to about 20, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • unit dosage forms comprising the compositions and formulations described herein. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed.
  • the pharmaceutical composition e.g ., a dosage or unit dosage form of a pharmaceutical composition
  • the pharmaceutical composition also includes one or more other compounds (or pharmaceutically acceptable salts thereof) that are useful for treating pulmonary hypertension.
  • the amount of a taxane (e.g ., paclitaxel) or a derivative thereof in the composition is included in any of the following ranges: about 5 to about 50 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • the amount of a taxane (e.g. , paclitaxel) or derivative thereof in the composition e.g.
  • a dosage or unit dosage form is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg, of the taxane (e.g ., paclitaxel) or derivative thereof.
  • the carrier is suitable for parental administration (e.g ., intravenous administration).
  • a rapamycin is not contained in the composition.
  • the taxane (e.g ., paclitaxel) or derivative thereof is the only pharmaceutically active agent for the treatment of pulmonary hypertension that is contained in the composition.
  • articles of manufacture comprising the compositions, formulations, and unit dosages described herein in suitable packaging for use in the methods of treatment, methods of administration, and dosage regimes described herein.
  • the articles of manufacture may be used to treat pulmonary hypertension.
  • the pulmonary hypertension is IPAH, FPAH, or APAH.
  • Suitable packaging for compositions described herein are known in the art, and include, for example, vials (such as sealed vials), vessels (such as sealed vessels), ampules, bottles, jars, flexible packaging ( e.g ., sealed Mylar or plastic bags), and the like. These articles of manufacture may further be sterilized and/or sealed.
  • the amount of rapamycin or a derivative thereof in the kit is included in any of the following ranges: about 5 mg to about 20 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • the amount of rapamycin or a derivative thereof in the kit is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
  • the kit includes one or more other compounds ( i . e ., one or more compounds other than a taxane) that are useful for treating pulmonary hypertension
  • Kits of the invention include one or more containers comprising a taxane (e.g ., paclitaxel) or a derivative thereof-containing nanoparticle compositions (formulations or unit dosage forms and/or articles of manufacture), and in some variations, further comprise instructions for use in accordance with any of the methods of treatment described herein.
  • the kit comprises i) a composition comprising nanoparticles comprising a taxane (e.g ., paclitaxel) and a carrier protein (such as albumin) and ii) instructions for administering the nanoparticles and the chemotherapeutic agents simultaneously and/or sequentially, for treatment of pulmonary hypertension.
  • the pulmonary hypertension is pulmonary arterial hypertension.
  • the pulmonary arterial hypertension is idiopathic pulmonary arterial hypertension.
  • the amount of a taxane (e.g ., paclitaxel) or a derivative thereof in the kit is included in any of the following ranges: about 5 mg to about 20 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • Kits may also be provided that contain sufficient dosages of rapamycin or a derivative thereof and/or a taxane (e.g ., paclitaxel) or a derivative thereof as disclosed herein to provide effective treatment for an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • a taxane e.g ., paclitaxel
  • the kit comprises a dry ( e.g ., lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form generally a stable aqueous suspension of nanoparticles comprising a taxane (e.g. , paclitaxel) or a derivative thereof and albumin ( e.g. , a taxane ( e.g. , paclitaxel) or a derivative thereof coated with albumin).
  • a dry e.g ., lyophilized composition
  • a taxane e.g. paclitaxel
  • albumin e.g. , a taxane ( e.g. , paclitaxel) or a derivative thereof coated with albumin.
  • kits of the invention are in suitable packaging.
  • suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g ., seled Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
  • compositions containing carrier proteins and poorly water soluble pharmaceutical agents are known in the art.
  • nanoparticles containing poorly water soluble pharmaceutical agents and carrier proteins e.g ., albumin
  • high shear forces e.g ., sonication, high pressure homogenization, or the like.
  • the organic solvent can be methylene chloride, chloroform/ethanol, or chloroform/t-butanol (for example with a ratio of about any of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1,2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1 or with a ratio of about any of 3:7, 5:7, 4:6, 5:5, 6:5, 8:5, 9:5, 9.5:5, 5:3, 7:3, 6:4, or 9.5:0.5).
  • a carrier protein e.g ., human serum albumin
  • the mixture is subjected to high pressure homogenization (e.g ., using an Avestin, APV Gaulin, MicrofluidizerTM such as a MicrofluidizerTM Processor M-110EH from Microfluidics, Stansted, or Ultra Turrax homogenizer).
  • the emulsion may be cycled through the high pressure homogenizer for between about 2 to about 100 cycles, such as about 5 to about 50 cycles or about 8 to about 20 cycles ( e.g ., about any of 8, 10, 12, 14, 16, 18 or 20 cycles).
  • the organic solvent can then be removed by evaporation utilizing suitable equipment known for this purpose, including, but not limited to, rotary evaporators, falling film evaporators, wiped film evaporators, spray driers, and the like that can be operated in batch mode or in continuous operation.
  • the solvent may be removed at reduced pressure (such as at about any of 25 mm Hg, 30 mm Hg, 40 mm Hg, 50 mm Hg, 100 mm Hg, 200 mm Hg, or 300 mm Hg).
  • the amount of time used to remove the solvent under reduced pressure may be adjusted based on the volume of the formulation. For example, for a formulation produced on a 300 mL scale, the solvent can be removed at about 1 to about 300 mm Hg ( e.g.
  • 25 % w/v can be added to adjust the human serum albumin to a taxane (e.g ., paclitaxel) ratio to about any of 18:1, 15,:1 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7.5:1, 7:1, 6:1, 5:1, 4:1, or 3:1.
  • a taxane e.g ., paclitaxel
  • human serum albumin solution e.g ., 25 % w/v
  • another solution is added to adjust the concentration of rapamycin in the dispersion to about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml.
  • the dispersion may be serially filtered through multiple filters, such as a combination of 1.2 ⁇ m and 0.8/0.2 ⁇ m filters; the combination of 1.2 ⁇ m, 0.8 ⁇ m, 0.45 ⁇ m, and 0.22 ⁇ m filters; or the combination of any other filters known in the art.
  • the dispersion obtained can be further lyophilized.
  • the nanoparticle compositions may be made using a batch process or a continuous process ( e.g ., the production of a composition on a large scale).
  • This additional agent can either be admixed with the taxane (e.g ., paclitaxel) and/or the carrier protein during preparation of the taxane ( e.g ., paclitaxel)/carrier protein composition, or added after the taxane ( e.g ., paclitaxel)/carrier protein composition is prepared.
  • the agent can be added along with an aqueous medium used to reconstitute/suspend the taxane ( e.g ., paclitaxel)/carrier protein composition or added to an aqueous suspension of the carrier protein-associated rapamycin.
  • Example 1 Exemplary Methods for the Formation of Nanoparticle Compositions with Rapamycin and Albumin.
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 8 mg/mL in the emulsion and the formulation was made on a 300 mL scale.
  • Rapamycin (2400 mg) was dissolved in 12 mL of chloroform/t-butanol. The solution was then added into 288 mL of a human serum albumin solution (1-8% w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was removed at 40 °C at reduced pressure (10-200 mm of Hg).
  • the dispersion was filtered through multiple filters.
  • the size of the filtered formulation was 85-100 nm (Z av , Malvern Zetasizer).
  • the dispersion was further lyophilized (FTS Systems, Dura-Dry ⁇ P, Stone Ridge, New York) for 60 hours.
  • the resulting cake was easily reconstitutable to the original dispersion by the addition of sterile water or 0.9 % (w/v) sterile saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 8.3 mg/mL in the emulsion and the formulation was made on a 200 mL scale.
  • Rapamycin (1660 mg) was dissolved in 8.5 mL of chloroform/ethanol. The solution was then added into 191.5 mL of a human serum albumin solution (6% w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (25 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 85 nm (Z av , Malvern Zetasizer).
  • the dispersion was further lyophilized (FTS Systems, Dura-Dry ⁇ P, Stone Ridge, New York) for 60 hours.
  • the resulting cake was easily reconstitutable to the original dispersion by addition of 0.9 % (w/v) sterile saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (25 mm of Hg).
  • human serum albumin solution was added to the dispersion and the volume of the dispersion was made to 400 mL to adjust the human serum albumin to rapamycin ratio and to adjust the rapamycin concentration.
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 99 nm (Z av , Malvern Zetasizer).
  • the dispersion was further lyophilized (FTS Systems, Dura-Dry ⁇ P, Stone Ridge, New York) for 60 hours.
  • the resulting cake was easily reconstitutable to the original dispersion by addition of 0.9 % (w/v) sterile saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 8.2 mg/mL in the emulsion and the formulation was made on a 40 mL scale.
  • Rapamycin (328 mg) was dissolved in 1.8 mL of chloroform/ethanol. The solution was then added into 38.2 mL of a human serum albumin solution (6% w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 108 nm (Z av , Malvern Zetasizer).
  • the liquid suspension was found to be stable at 4 °C and 25 °C at least for 48 hours.
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 9.2 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin (184 mg) was dissolved in 1.0 mL of chloroform/ethanol. The solution was then added into 19.0 mL of a human serum albumin solution (7 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 124 nm (Z av , Malvern Zetasizer).
  • the liquid suspension was found to be stable at 4 °C and 25 °C at least for 24 hours.
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 8.4 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin (168 mg) was dissolved in 1.2 mL of chloroform/ethanol. The solution was then added into 18.8 mL of a human serum albumin solution (6 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 95 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 8.2 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 164 mg was dissolved in 0.9 mL of chloroform/ethanol. The solution was then added into 19.1 mL of a human serum albumin solution (8 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 149 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 6.6 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 132 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (5 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 129 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 108 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (1 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 99 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 5.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 100 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 146 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the resulting dispersion was a white milky suspension.
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 129 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 166 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 90 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin in which the rapamycin concentration was 4.0 mg/mL in the emulsion and the formulation was made on a 20 mL scale.
  • Rapamycin 80 mg was dissolved in 0.8 mL of chloroform/ethanol. The solution was then added into 19.2 mL of a human serum albumin solution (3 % w/v). The mixture was homogenized for 5 minutes at 10,000 rpm (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 20,000 psi while recycling the emulsion.
  • the resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (40 mm of Hg).
  • the dispersion was serially filtered.
  • the size of the 0.22 ⁇ m filtered formulation was 81 nm (Z av , Malvern Zetasizer).
  • This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and albumin.
  • Rapamycin (30 mg) was dissolved in 2 ml chloroform/ethanol. The solution was then added into 27.0 ml of a human serum albumin solution (3% w/v). The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system was transferred into a Rotavap, and the solvent was rapidly removed at 40 °C at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • compositions of the invention e.g., compositions that contain rapamycin derivatives or carrier proteins other than human serum albumin
  • compositions that contain rapamycin derivatives or carrier proteins other than human serum albumin can be made using these methods or a variation of these methods. It should be recognized that the amounts, types, and proportions of drug, solvents, and proteins used in these examples are not limiting in any way.
  • Example 2 Exemplary Methods for the Formation of Nanoparticle Compositions with Paclitaxel and Albumin.
  • This example provides formulations of paclitaxel/albumin.
  • the compositions were prepared essentially as described in U.S. Pat. No. 5,439,686 and 5,916,596 . Briefly, paclitaxel was dissolved in an organic solvent (such as methylene chloride or a chloroform/ethanol mixture), and the solution was added to a human serum albumin solution. The mixture was homogenized for 5 minutes at low RPM to form a crude emulsion, and then transferred into a high pressure homogenizer. The emulsification was performed at 9000 - 40,000 psi while recycling the emulsion for at least 5 cycles.
  • an organic solvent such as methylene chloride or a chloroform/ethanol mixture
  • the resulting system was transferred into a rotary evaporator, and the organic solvent was rapidly removed at 40 °C, at reduced pressure (30 mm Hg) for 20-30 minutes. The dispersion was then further lyophilized for 48 hours. The resulting cake was reconstituted to the original dispersion by addition of sterile water or saline, which may optionally contain additional antimicrobial agent(s).
  • the overall toxicity of Nab -rapamycin was determined in a dose ranging study in Sprague Dawley rats.
  • the dose levels of Nab -rapamycin used were 0, 15, 30, 45, 90 and 180 mg/kg with a q4dx3 schedule.
  • Blood samples were collected prior to dosing (baseline) and post-dosing at the following time points: 1, 5, 10, 15, 30 and 45 minutes, and 1, 4, 8, 24, 36 and 48 hours. Plasma samples were analyzed for rapamycin using LC/MS.
  • Nab -rapamycin was nontoxic at the highest dose of 180 mg/kg on a q4dx3 schedule. No changes in blood chemistry or CBC were observed. No hypercholesterolemia and hypertriglyceridemia were observed. As illustrated in Figures 1 and 2C , Nab -rapamycin exhibited linear pharmacokinetics with respect to dose and rapid extravascular distribution as demonstrated by large Vss and Vz. The Cmax and AUCinf of Nab -rapamycin were dose proportional ( Figures 2A and 2B , respectively).
  • PE 50 polyethylene catheter
  • PE 50 polyethylene catheter
  • a second catheter PE 50 is advanced under X-ray guidance into the pulmonary artery to measure pulmonary artery pressure.
  • Baseline measurements pressures, ECG, pulmonary flow, TEE is obtained. Based upon the PA velocity profile, pulmonary artery pressure is estimated for the echo measurements. After baseline measurements, the rats receive Nab -rapamycin, Nab -paclitaxel, and the combination of Nab -rapamycin and Nab -paclitaxel to test the does-response range.
  • Example 6 Response to Nab -rapamycin, Nab -paclitaxel, and the combination of Nab -rapamycin and Nab -paclitaxel in Primary Chronic Pulmonary Hypertension Model
  • Rats are anesthetized with sodium pentobarbital (80 mg/kg subcutaneously SC), ketamine (40 mg/kg, IM), and atropine (0.28 mg/kg, IP) followed by 2000 U heparin IP (Sigma Chemical). Anesthesia is maintained with 2.5-5.0 mg of pentobarbital SC every 30-60 minutes as needed. Blood temperature is maintained at 38-39°C with a heating pad. During surgery, 60% oxygen is delivered via a flow-by mask.
  • a catheter (PE 90) is inserted into a vein.
  • Baseline TEE is obtained.
  • the rats are daily observed.
  • the following increasing doses are used: Nab -rapamycin (e.g ., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg), Nab -paclitaxel (e.g.
  • Nab -rapamycin and Nab -paclitaxel e.g., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg of Nab -rapamycin or Nab- paclitaxel administered daily and weekly.
  • Nab -rapamycin and Nab -paclitaxel e.g., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg of Nab -rapamycin or Nab- paclitaxel
  • data is recorded after 15-20 min stabilization.
  • control group data is obtained at equivalent time points.
  • all animals are allowed to recover and will be returned to its cage.
  • Rats are anesthetized with sodium pentobarbital (80 mg/kg subcutaneously SC), ketamine (40 mg/kg, IM), and atropine (0.28 mg/kg, IP) followed by 2000 U heparin IP (Sigma Chemical). Anesthesia is maintained with 2.5-5.0 mg of pentobarbital SC every 30-60 minutes as needed. Blood temperature is maintained at 38-39°C with a heating pad. During surgery, 60% oxygen is delivered via a flow-by mask.
  • the left carotid artery is isolated and an incision made, and a polyethylene catheter (PE 50) is inserted to record arterial pressure.
  • a polyethylene catheter (PE 50) is inserted to record arterial pressure.
  • a second catheter (PE 50) is advanced under X-ray guidance into the pulmonary artery to measure pulmonary artery pressure.
  • Baseline measurements pressures, ECG, pulmonary flow, TEE are obtained. After baseline measurements, the rats receive no drugs (control group) or either Nab -rapamycin, Nab -paclitaxel, or the combination of Nab -rapamycin and Nab -paclitaxel (as previously assigned).
  • Nab -rapamycin e.g ., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg
  • Nab -paclitaxel e.g ., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg
  • Nab -rapamycin and Nab -paclitaxel e.g., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg of Nab -rapamycin and/or Nab -paclitaxel
  • Example 7 Response to Nab -rapamycin, Nab -paclitaxel, and the combination of Nab -rapamycin and Nab -paclitaxel in Pulmonary Hypertension Model
  • Study Sample Forty pathogen-free, 13-wk-old, male Sprague-Dawley rats (body weight, 350-400 g) are studied.
  • Rats are anesthetized with atropine sulfate (50 ⁇ g, intramuscular), ketamine hydrochloride (10 mg, intramuscular), and xylazine (3 mg, subcutaneous).
  • atropine sulfate 50 ⁇ g, intramuscular
  • ketamine hydrochloride 10 mg, intramuscular
  • xylazine 3 mg, subcutaneous.
  • anesthesia is maintained with halothane inhalation (0.5%) and rats are ventilated with a Harvard rodent ventilator (tidal volume, 3.0 ml; respiratory rate, 60/min; positive end-expiratory pressure [PEEP], 1 cm H2O) (Type 683; Harvard Apparatus, South Natick, MA).
  • PEEP positive end-expiratory pressure
  • mice are injected subcutaneously in the right hindlimb with monocrotaline (MCT, 60 mg/kg; Sigma, St. Louis, MO) (MCT is dissolved in distilled water, adjusted to pH 7.40 with 0.5 N HCl).
  • MCT monocrotaline
  • Rats are randomized to receive either Nab -rapamycin, Nab- paclitaxel, or the combination of Nab -rapamycin and Nab -paclitaxel, or vehicle by intravenous administration.
  • rats are anesthetized by intramuscular injections of atropine sulfate (50 ⁇ g, intramuscular) and ketamine hydrochloride (10 mg, intramuscular) and are placed in the supine position. Anesthesia is maintained with inhalation halothane (0.5%, by hood).
  • a carotid arterial catheter PE-50, 0.58-mm i.d.
  • a pulmonary artery catheter (PV 1, 0.28-mm i.d.) is inserted into the right internal jugular vein through an introducer. The pulmonary artery catheter is passed (under pressure wave guidance) through the right ventricle into the pulmonary artery.
  • Right ventricular systolic pressure measurements are also obtained by percutaneous needle (27 gauge) puncture of the right ventricle. Mean arterial blood pressure, pulmonary artery blood pressure, and right ventricular systolic blood pressure are recorded. After exsanguination, the right lung, right ventricle, left ventricle plus septum, liver, spleen, kidney, testis, and thymus are collected for histology. Tissues are fixed in 10% neutral buffered formalin. The lungs are axially sectioned, processed, and embedded in paraffin wax. Five-micron sections are prepared and stained with elastin-van Gieson (EVG). The severity of neointimal formation is scored.
  • EMG elastin-van Gieson
  • the right lung, right ventricle, left ventricle plus septum, liver, spleen, kidney, testis, and thymus are collected for histology. Tissues are fixed in 10% neutral buffered formalin. The lungs are axially sectioned, processed, and embedded in paraffin wax. Five-micron sections are prepared and stained with elastin-van Gieson (EVG). The severity of neointimal formation is scored. Briefly, the absence of neointimal formation equals 0; the presence of neointimal proliferation causing less than 50% lumenal narrowing equals 1; lumenal narrowing greater than 50% equals 2.
  • EMG elastin-van Gieson
  • mice C57BL/6 mice are obtained and used at 6-8 weeks of age. The animals are fed standard mouse chow and are allowed to take food and water ad libidum. All experiments conform to the NIH guidelines to the care and use of experimental animals.
  • Nab- rapamycin e.g., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg
  • Nab- paclitaxel e.g., between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg
  • Nab- rapamycin and Nab -paclitaxel e.g. , between about 0.5-30 mg/kg, such as about 1, 2.5, 5, 7.5 or 10 mg/kg of Nab -rapamycin and/or Nab -paclitaxel
  • the right lung, right ventricle, left ventricle plus septum, liver, spleen, kidney, testis, and thymus are collected for histology. Tissues are fixed in 10% neutral buffered formalin. The lungs are axially sectioned, processed, and embedded in paraffin wax. Five-micron sections are prepared and stained with elastin-van Gieson (EVG). The severity of neointimal formation is scored. Briefly, the absence of neointimal formation equals 0; the presence of neointimal proliferation causing less than 50% lumenal narrowing equals 1; lumenal narrowing greater than 50% equals 2.
  • EMG elastin-van Gieson
  • mice C57BL/6 mice are obtained and used at 6-8 weeks of age. The animals are fed standard mouse chow and are allowed to take food and water ad libidum. All experiments conform to the NIH guidelines to the care and use of experimental animals.
  • Example 13 Clinical Use of Nab -rapamycin and Nab -paclitaxel for treatment of Severe Pulmonary Arterial Hypertension
  • Dose Limiting Toxicity is considered to be a Grade 3 or 4 non-hematologic toxicity or a Grade 4 hematologic toxicity.
  • This example demonstrates intrapulmonary delivery of a pharmaceutical composition comprising Nab -paclitaxel (ABI-007).
  • the purpose of this study was to determine the time course of [ 3 H]ABI-007 in blood and select tissues following intratracheal instillation to Sprague Dawley rats.
  • the target volume of the intratracheal dose formulation to be administered to the animals was calculated based on a dose volume of 1.5 mL per kg body weight.
  • the dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1-mL gas-tight, luer-lock syringe. The appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing. The average dose for all animals was 4.7738+/-0.0060 (CV 1.5059) mg paclitaxel per kg body weight.
  • Tritium derived from [ 3 H]ABI-007 is rapidly absorbed after intratracheal instillation.
  • the average absorption and elimination half-lives (k01 half-life and k10 half-life, respectively) for tritium in blood after an intratracheal dose of [ 3 H]ABI-007 (mean +/-SD) were 0.0155+/-0.0058 hr and 4.738+/-0.366 hr, respectively.
  • the average apparent clearance of tritium from blood was 0.1235+/-0.0180 L/hr (see Table 1 above).
  • a fair amount of radioactivity was present in the gastrointestinal tract (including contents) at 24 hr post dosing (27% for the intratracheal dose).
  • the presence of tritium in the gastrointestinal tract may be due to biliary excretion or clearance of tritium from the respiratory tract via mucociliary clearance with subsequent swallowing.
  • This example demonstrates an investigation of Aerotech II and Pari nebulizers for pulmonary delivery of pharmaceutical compositions comprising Nab -paclitaxel.
  • the nanoparticle/albumin formulation of paclitaxel shows excellent bioavailability in rats when administered by the pulmonary route. There were no overt signs of early toxicity at the administered dose.
  • Pulmonary delivery of Nab -paclitaxel (ABI-007) may be achieved using conventional nebulizers to treat diseases such as pulmonary hypertension.
  • This example describes intrapulmonary delivery of a pharmaceutical composition comprising Nab -rapamycin.
  • the purpose of this study was to determine the pulmonary absorption of Nab -rapamycin in blood following intratracheal instillation to Sprague Dawley rats as compared to intravenous installation.
  • the target volume of the intratracheal dose formulation that was administered to the animals was calculated based on a dose volume of 1 mL per kg body.
  • the intratracheal dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1 mL gas-tight, luer-lock syringe.
  • the appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing.
  • samples were collected from the indwelling jugular cannulas of rats at the following predetermined post-dosing time points: 1, 5, 10, 15, 30, and 45 minutes (min) and 1, 4, 8, and 24 hours (h). All blood samples analyzed were dispensed into pre-weighed sample tubes, and the sample tubes were reweighed, and the weight of each sample was calculated by subtraction. The blood samples collected were assayed for total rapamycin concentration using LC/MS/MS.
  • This example demonstrates tissue distribution of Nab -rapamycin after intrapulmonary administration of a pharmaceutical composition comprising Nab -rapamycin in prepared in accordance with the present invention.
  • the purpose of this study was to determine the pulmonary absorption of Nab -rapamycin in tissue following intratracheal instillation to Sprague Dawley rats as compared to intravenous installation.
  • the target volume of the intratracheal dose formulation that was administered to the animals was calculated based on a dose volume of 1 mL per kg body.
  • the dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1-mL gas-tight, luer-lock syringe. The appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing.
  • rapamycin concentration is greater in lung tissue when delivered via pulmonary as compared to intravenous delivery.
  • the total concentration of rapamycin in the brain was lower when delivered via intratracheal (IT) as compared to intravenous (IV).
  • IT intratracheal
  • IV intravenous
  • pulmonary delivery of Nab -rapamycin may be suitable for the treatment of conditions such as pulmonary hypertension, wherein high local concentration of rapamycin would be beneficial.
  • Example 18 Formulation for Inhalation of Nab -rapamycin and Nab -paclitaxel
  • Nab -rapamycin and Nab -paclitaxel are prepared using microparticle techniques to yield effective formulations for dry powder inhalers (DPI). Starting with paclitaxel or rapamycin, a dry formulation is prepared of appropriate particle size and release characteristics to ensure efficacious delivery in the respiratory system.
  • DPI dry powder inhalers
  • the formulation is prepared using sonication techniques, or homogenization in which the active drug, dissolved in solvent, is dispersed into an aqueous protein solution to form an emulsion of nanoparticles. This emulsion is then evaporated to remove solvents, leaving the active drug coated with protein in solution.
  • This liquid sample containing the colloidal drug particles is measured by Malvern Zetasizer and gives a Z-average size of 260 nm. In a preferred embodiment, the range of sizes of these colloidal particles is about 50-1,000 nm, and more preferably about 70-400 nm.
  • This spray dried powder is then mixed with an excipient carrier powder.
  • an excipient carrier powder including lactose, trehalose, Pharmatose 325 M, sucrose, mannitol, and the like.
  • the size of the carrier powder is significantly larger than that of the formulated drug particles ( ⁇ 63-90 ⁇ m for lactose, 40-100 ⁇ m for Pharmatose).
  • Example 19 Clinical Use of Nab -paclitaxel for treatment of Severe (NYHA III or IV) Pulmonary Arterial Hypertension
  • a 20-gauge heparin-bonded cannula inserted percutaneously into a radial, brachial, or femoral artery is used for blood sampling and monitoring of systemic arterial pressure.
  • Mean vascular pressure levels are determined by electronic integration of the pressure signals.
  • Heart rate and vascular pressures are monitored continuously.
  • Cardiac output is measured in triplicate by thermodilution or by the Fick method with measured oxygen consumption.
  • Systemic and pulmonary vascular resistances are calculated using the mean cardiac index and mean vascular pressures.
  • DLT a doubling of LFT values above baseline that is confirmed at 24 hour and 48 hour time points and not related to progression of underlying disease in the opinion of the investigator. It is anticipated that this patient population would have severe dyspnea at baseline related to disease. In fact, this is part of what defines the patient population studied. Therefore, worsening dyspnea that worsens NYHA Class or requires ventilator support and not related to progression of underlying disease in the opinion of the investigator is considered a DLT. It is anticipated that this patient population would have hypoxia requiring oxygen therapy at rest as part of the disease process; therefore, increasing oxygen requirements of >2 lpm above baseline or need for initiating positive pressure ventilation is considered a DLT.
  • Subjects at monthly intervals (at end of each drug cycle) undergo clinical testing and procedures including physical exam, recording vitals signs, assessment of NYHA/WHO functional class, venous blood drawn for coagulation panel, lipid panel, NT-pro BNP and CRP, 6MWT (with assessment of Borg dyspnea index), and echocardiogram with assessment of TRV LV and RV function.
  • Subjects at week 16 undergo clinical testing and procedures including pulmonary function tests, cardiac MRI, and right heart catheterization.
  • the pulmonary artery catheter is a triple lumen central venous catheter with two lumens devoted to the pressure transduction functions.
  • the distal port transduces pressure from the pulmonary artery and from the left atrium, when in the "wedge" position.
  • the central venous port transduces right atrial pressures.
  • right ventricular pressures are transduced. Warmed coils on the catheter and a thermister at the catheter tip allows for continuous, thermal dilution, cardiac output measurements, which complement mixed venous blood saturation for cardiac output calculation by the Fick method.
  • the MRI also provides estimates of myocardial mass and quantitative right ventricular measurements not attainable by 2-D echocardiography.
  • the gradients are operated at slew rates that do not result in skeletal muscle stimulation, and the radiofrequency deposition is at or below FDA limits. Patients are asked to report sensations of muscle twitches or warmth during the scan. These measurements are performed at baseline and at the completion of therapy with Nab -paclitaxel.
  • Samples and data collected under this protocol are used to develop the safety profile of Nab -paclitaxel in patients with severe PAH who are NYHA class III or IV despite best available therapy. They are also used to evaluate dosing regimen of Nab -paclitaxel in patients with severe PAH by monitoring hematologic data and symptom profile.
  • PAH Mean Pulmonary Artery Pressure
  • PCOP Pulmonary Capillary Occlusion Pressure
  • LVEDP Left Ventricular End Diastolic Pressure
  • PVR Pulmonary Vascular Resistance
  • patients must be IPAH, FPAH, or APAH
  • PAH therapy including: (a) a Prostacyclin (IV epoprostenol, IV or subcutaneous remodulin, inhaled iloprost) unless unwilling or unable to tolerate therapy, (b) phosphodiesterase type 5 inhibitor (sildenafil), (c) endothelin receptor antagonist (Ambrisenten) or (d) any combination of a-c, (6) NYHA class III or IV despite 3
  • Target patients are those with severe PAH (NYHA class III or IV) despite best available therapy.
  • Best available therapy includes a Prostacyclin (unless unwilling or unable to tolerate) and at least one oral agent (e.g., an endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor).
  • subjects participate in a physical examination, baseline laboratory testing, pulmonary function studies, chest X-ray, 6MWT, Borg dyspnea scoring (for baseline exercise capacity and assessment of NYHA/WHO functional class), and a cardiac MRI.
  • a 20-gauge heparin-bonded cannula inserted percutaneously into a radial, brachial, or femoral artery is used for blood sampling and monitoring of systemic arterial pressure.
  • Mean vascular pressure levels are determined by electronic integration of the pressure signals.
  • Heart rate and vascular pressures are monitored continuously.
  • Cardiac output is measured in triplicate by thermodilution or by the Fick method with measured oxygen consumption.
  • Systemic and pulmonary vascular resistances are calculated using the mean cardiac index and mean vascular pressures.
  • the Treatment Stage of the trial is designed to test the safety, dosing, and potential efficacy of Nab -rapamycin in patients with severe PAH.
  • Anti-proliferative therapy includes Nab -rapamycin administered by IV infusion over 30 minutes (alternatively, any of 1, 5, 10, 15, or 20 minutes) once per week for 3 weeks.
  • One cycle consists of 3 doses of Nab- rapamycin over three weeks and one week of rest. Patients undergo 4 cycles per 16 weeks. The initial group of subjects receives 30 mg/m2 of Nab -rapamycin.
  • Dosing is escalated according to a standard 3x3 rule. 3 patients are enrolled at Dose 1. If no Dose Limiting Toxicity (DLT) occurs, then 3 patients are enrolled at next dose level and so on. If a DLT occurs, then 3 additional patients are enrolled at that level. If no more than 2/6 of the same DLT occur, then the next dose cohort is opened. If an intolerable DLT thought to be secondary to Nab -rapamycin occurs, then the individual patient has dose reduction to next lower dose level.
  • the various dosing groups include dosages ranging from 30-250 mg/m 2 such as 30 mg/m 2 , 60 mg/m 2 , 80 mg/m 2 , and 100 mg/m 2 .
  • Prophylaxis may be provided including administration of 8 mg of Ondansetron 30 minutes prior to drug infusion and q12 hours x 2 doses after infusion. Lorazepam or Promethazine may also be used as needed for breakthrough nausea/vomiting.
  • Subjects at weekly or at other appropriate intervals undergo clinical testing and procedures including recording vital signs, neurotoxicity monitoring with West-Hand Esthesiometer and score sheet, adverse event monitoring, assessment of concomitant medications, standard chemistries, and venous blood drawn for CBC and, as necessary, to monitor coagulation profile if patient is on coumadin therapy.
  • Samples and data collected under this protocol are used to develop the safety profile of Nab -rapamycin in patients with severe PAH who are NYHA class III or IV despite best available therapy. They are also used to evaluate dosing regimen of Nab -rapamycin in patients with severe PAH by monitoring hematologic data and symptom profile.
  • a complete set of vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation on room air if>88% and baseline oxygen level, height, and weight), monitoring for adverse events including filament testing for neurotoxicity and assessment of concomitant medication use are taken every week of the trial on the day of drug infusion.
  • Laboratory monitoring include a CBC with differential and Chem 20 drawn every week after initiation of study drug to monitor for hematologic, renal and liver adverse effect of drug therapy. At the end of the fourth cycle repeat CBC with differential, Chem 20, coagulation panel, lipid panel BNP and CRP are drawn. For patients on coumadin, coagulation labs are drawn at least once per week for four weeks to monitor for need to titrate dose.
  • Echocardiogram and 6MWT are generally performed every four weeks. At the end of the fourth cycle of drug therapy (16 weeks or other period as appropriate), repeat screening tests are performed including right heart catheterization, echocardiogram, full pulmonary function testing, 6MWT, CXR and cardiopulmonary MRI.
  • an individual with pulmonary hypertension is administered (a) nanoparticles comprising paclitaxel and albumin, and (b) nanoparticles comprising rapamycin and albumin.
  • the application discloses inter alia following items:

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP17191332.0A 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie Withdrawn EP3326630A3 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US92772907P 2007-05-03 2007-05-03
EP08767585A EP2146707A2 (de) 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie
PCT/US2008/005792 WO2008137148A2 (en) 2007-05-03 2008-05-05 Methods and compositions for treating pulmonary hypertension

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP08767585A Division EP2146707A2 (de) 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie

Publications (2)

Publication Number Publication Date
EP3326630A2 true EP3326630A2 (de) 2018-05-30
EP3326630A3 EP3326630A3 (de) 2018-08-29

Family

ID=39637592

Family Applications (2)

Application Number Title Priority Date Filing Date
EP08767585A Withdrawn EP2146707A2 (de) 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie
EP17191332.0A Withdrawn EP3326630A3 (de) 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP08767585A Withdrawn EP2146707A2 (de) 2007-05-03 2008-05-05 Verfahren und zusammensetzungen zur behandlung pulmonaler hypertonie

Country Status (5)

Country Link
US (4) US20100166869A1 (de)
EP (2) EP2146707A2 (de)
CA (1) CA2686736A1 (de)
HK (1) HK1255083A1 (de)
WO (1) WO2008137148A2 (de)

Families Citing this family (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5439686A (en) * 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US20030199425A1 (en) * 1997-06-27 2003-10-23 Desai Neil P. Compositions and methods for treatment of hyperplasia
US8853260B2 (en) 1997-06-27 2014-10-07 Abraxis Bioscience, Llc Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
EP3470084A1 (de) 2002-12-09 2019-04-17 Abraxis BioScience, LLC Zusammensetzungen enthaltend albuminnanopartikel und methoden zur freisetzung von wirkstoffen
US8735394B2 (en) * 2005-02-18 2014-05-27 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
EP1853250B1 (de) 2005-02-18 2011-11-02 Abraxis BioScience, LLC Kombinationen und modi zur verabreichung therapeutischer mittel und kombinationstherapie
JP5756588B2 (ja) 2005-07-15 2015-07-29 ミセル テクノロジーズ、インコーポレイテッド 制御されたモルホロジーの薬剤粉末を含むポリマーコーティング
WO2007011708A2 (en) 2005-07-15 2007-01-25 Micell Technologies, Inc. Stent with polymer coating containing amorphous rapamycin
RU2451510C2 (ru) 2005-08-31 2012-05-27 АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи Композиции и способы получения слаборастворимых в воде лекарственных средств с увеличенной стабильностью
CA2650590C (en) 2006-04-26 2018-04-03 Micell Technologies, Inc. Coatings containing multiple drugs
CA2667228C (en) 2006-10-23 2015-07-14 Micell Technologies, Inc. Holder for electrically charging a substrate during coating
ES2700074T3 (es) 2006-12-14 2019-02-13 Abraxis Bioscience Llc Terapia para el cáncer de mama sobre la base del estado de los receptores hormonales con nanopartículas que comprenden taxano
CN101711137B (zh) 2007-01-08 2014-10-22 米歇尔技术公司 具有可生物降解层的支架
US11426494B2 (en) 2007-01-08 2022-08-30 MT Acquisition Holdings LLC Stents having biodegradable layers
NZ621972A (en) 2007-03-07 2015-09-25 Abraxis Bioscience Llc Nanoparticle comprising rapamycin and albumin as anticancer agent
AU2008256684B2 (en) 2007-05-25 2012-06-14 Micell Technologies, Inc. Polymer films for medical device coating
PL2155188T3 (pl) 2007-06-01 2014-03-31 Abraxis Bioscience Llc Sposoby i kompozycje do leczenia nawrotowego raka
US20100298928A1 (en) * 2007-10-19 2010-11-25 Micell Technologies, Inc. Drug Coated Stents
MX2010011165A (es) * 2008-04-10 2011-02-22 Abraxis Bioscience Llc Composiciones de derivados de taxano hidrofobos y sus usos.
SG192523A1 (en) 2008-04-17 2013-08-30 Micell Technologies Inc Stents having bioabsorbable layers
JP2011528275A (ja) 2008-07-17 2011-11-17 ミセル テクノロジーズ，インク． 薬物送達医療デバイス
US9510856B2 (en) 2008-07-17 2016-12-06 Micell Technologies, Inc. Drug delivery medical device
ES2668837T3 (es) 2008-12-11 2018-05-22 Abraxis Bioscience, Llc Terapia de combinación que incluye un taxano y un agente terapéutico adicional
US8834913B2 (en) 2008-12-26 2014-09-16 Battelle Memorial Institute Medical implants and methods of making medical implants
CN102427728A (zh) 2009-03-13 2012-04-25 阿布拉科斯生物科学有限公司 用硫代秋水仙碱衍生物进行联合治疗
FR2943539B1 (fr) * 2009-03-31 2011-07-22 Ethypharm Sa Composition pharmaceutique comprenant un macrolide immunosuppresseur de la famille des limus.
WO2010120552A2 (en) 2009-04-01 2010-10-21 Micell Technologies, Inc. Coated stents
EA023244B1 (ru) 2009-04-10 2016-05-31 Хаян Ки Способ предотвращения старения клеток
CA2758913A1 (en) 2009-04-15 2010-10-21 Abraxis Bioscience, Llc Prion free nanoparticle compositions and methods of making thereof
WO2010121187A2 (en) 2009-04-17 2010-10-21 Micell Techologies, Inc. Stents having controlled elution
SG178873A1 (en) 2009-08-25 2012-04-27 Abraxis Bioscience Llc Combination therapy with nanoparticle compositions of taxane and hedgehog inhibitors
EP2531140B1 (de) 2010-02-02 2017-11-01 Micell Technologies, Inc. Stent und stenteinsatzsystem mit verbesserter einsetzbarkeit
US8795762B2 (en) 2010-03-26 2014-08-05 Battelle Memorial Institute System and method for enhanced electrostatic deposition and surface coatings
KR101786142B1 (ko) 2010-03-26 2017-10-17 아브락시스 바이오사이언스, 엘엘씨 간세포 암종의 치료 방법
WO2011123395A1 (en) 2010-03-29 2011-10-06 Abraxis Bioscience, Llc Methods of treating cancer
ES2925531T3 (es) 2010-03-29 2022-10-18 Abraxis Bioscience Llc Procedimientos para mejorar la administración de fármacos y la eficacia de agentes terapéuticos
EP2560576B1 (de) 2010-04-22 2018-07-18 Micell Technologies, Inc. Stents und andere vorrichtungen mit beschichtung durch eine extrazelluläre matrix
BR112012030699A2 (pt) 2010-06-02 2016-09-13 Abraxis Bioscience Llc métodos para tratar câncer de bexiga
CA2801645A1 (en) 2010-06-04 2011-12-08 Abraxis Bioscience, Llc Use of nanoparticules comprising a taxane and an albumin in the treatment of pancreatic cancer
MY166014A (en) 2010-06-07 2018-05-21 Abraxis Bioscience Llc Combination therapy methods for treating proliferative diseases
EP2582682B1 (de) * 2010-06-17 2015-01-14 Cytokinetics, Inc. Mitotische kinesin-hemmer zur behandlung der pulmonalen arteriellen hypertonie
WO2012009684A2 (en) 2010-07-16 2012-01-19 Micell Technologies, Inc. Drug delivery medical device
US20120237550A1 (en) * 2011-03-16 2012-09-20 Siemens Healthcare Diagnostics Inc. Maintaining Antibody-Binding Activity Of Immunosuppressant Drug Conjugates
KR20200051841A (ko) * 2011-04-28 2020-05-13 아브락시스 바이오사이언스, 엘엘씨 나노입자 조성물의 혈관내 전달 및 그의 용도
WO2012166819A1 (en) 2011-05-31 2012-12-06 Micell Technologies, Inc. System and process for formation of a time-released, drug-eluting transferable coating
WO2013012689A1 (en) 2011-07-15 2013-01-24 Micell Technologies, Inc. Drug delivery medical device
US10188772B2 (en) 2011-10-18 2019-01-29 Micell Technologies, Inc. Drug delivery medical device
EP3560486A1 (de) 2011-12-14 2019-10-30 Abraxis BioScience, LLC Verwendung von polymeren hilfsstoffen zum gefriertrocknen oder gefrieren von partikeln
US9149455B2 (en) 2012-11-09 2015-10-06 Abraxis Bioscience, Llc Methods of treating melanoma
MX355422B (es) * 2012-11-14 2018-04-18 BIAL PORTELA & Cª S A Derivados de 1,3-dihidroimidazol-2-tiona para el uso en el tratamiento de hipertension arterial pulmonar y daño pulmonar.
US9511046B2 (en) 2013-01-11 2016-12-06 Abraxis Bioscience, Llc Methods of treating pancreatic cancer
ES2797376T3 (es) 2013-01-24 2020-12-02 Palvella Therapeutics Inc Composiciones para la administración transdérmica de inhibidores de mTOR
NZ630239A (en) 2013-02-11 2017-08-25 Abraxis Bioscience Llc Methods of treating melanoma
CN110279864A (zh) 2013-03-12 2019-09-27 阿布拉科斯生物科学有限公司 治疗肺癌的方法
EP2967803B1 (de) 2013-03-12 2023-12-27 Micell Technologies, Inc. Bioabsorbierbare biomedizinische implantate
MX2015011783A (es) 2013-03-13 2015-12-01 Abraxis Bioscience Llc Metodos para tratar tumores solidos pediatricos.
BR112015022047A8 (pt) 2013-03-14 2019-12-10 Abraxis Bioscience Llc uso de uma composição compreendendo nanopartículas contendo um fármaco da família limo e uma albumina
EP2996629B1 (de) 2013-05-15 2021-09-22 Micell Technologies, Inc. Bioabsorbierbare biomedizinische implantate
JP6529012B2 (ja) * 2013-10-08 2019-06-12 エイアイ・セラピューティクス・インコーポレーテッド リンパ脈管筋腫症の処置のためのラパマイシン
AU2015217349A1 (en) * 2014-02-11 2016-09-08 AI Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
US10307371B2 (en) 2014-02-11 2019-06-04 AI Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
US20170014341A1 (en) * 2014-04-04 2017-01-19 Lam Therapeutics, Inc. An Inhalable Rapamycin Formulation for Treating Age-Related Conditions
CN107249576A (zh) * 2014-10-07 2017-10-13 拉姆医疗公司 用于治疗肺高压的可吸入雷帕霉素制剂
MA40910A (fr) 2014-11-07 2017-09-12 Civitas Therapeutics Inc Poudres de rapamycine pour administration pulmonaire
US10527604B1 (en) 2015-03-05 2020-01-07 Abraxis Bioscience, Llc Methods of assessing suitability of use of pharmaceutical compositions of albumin and paclitaxel
US10705070B1 (en) 2015-03-05 2020-07-07 Abraxis Bioscience, Llc Methods of assessing suitability of use of pharmaceutical compositions of albumin and poorly water soluble drug
US10751319B2 (en) 2015-06-04 2020-08-25 Crititech, Inc. Collection device and methods for use
SI3313401T1 (sl) 2015-06-29 2022-04-29 Abraxis Bioscience, Llc Nanodelci, ki vsebujejo sirolim in albumin, za uporabo pri zdravljenju tumorjev epiteloidnih celic
PT3439635T (pt) 2016-04-04 2021-02-11 Crititech Inc Formulações para tratamento de tumores sólidos
BR112019006113A2 (pt) * 2016-09-28 2019-06-18 Abraxis Bioscience Llc métodos de tratamento de distúrbios mitocondriais e metabólicos
US10722499B2 (en) 2017-01-06 2020-07-28 Palvella Therapeutics, Inc. Anyhydrous compositions of mTOR inhibitors and methods of use
EP3615145B1 (de) 2017-06-09 2024-05-15 Crititech, Inc. Zusammensetzungen zur verwendung bei der behandlung von epithelzysten durch intracystische injektion antineoplastischer partikeln
JP6840869B2 (ja) * 2017-06-14 2021-03-10 クリチテック，インコーポレイテッド 肺障害の治療方法
EP3453385A1 (de) 2017-09-07 2019-03-13 Justus-Liebig-Universität Gießen Erfindung betreffend nanopartikel enthaltend taxane zur inhalativen applikation
CN118649239A (zh) 2017-10-03 2024-09-17 克里蒂泰克公司 局部递送抗肿瘤颗粒与全身递送免疫治疗剂相结合用于治疗癌症
WO2019183146A1 (en) 2018-03-20 2019-09-26 Abraxis Bioscience, Llc Methods of treating central nervous system disorders via administration of nanoparticles of an mtor inhibitor and an albumin
KR20210024471A (ko) * 2018-05-22 2021-03-05 아브락시스 바이오사이언스, 엘엘씨 폐고혈압을 치료하기 위한 방법 및 조성물
EP3817743A4 (de) 2018-07-02 2022-07-06 Palvella Therapeutics, Inc. Wasserfreie zusammensetzungen von mtor-hemmern und verfahren zur verwendung
WO2020191053A1 (en) * 2019-03-19 2020-09-24 Abraxis Bioscience, Llc Subcutaneous administration of nanoparticles comprising an mtor inhibitor and albumin for treatment of diseases
JP2022541456A (ja) * 2019-07-15 2022-09-26 イエール ユニバーシティ 肺動脈性肺高血圧症を処置するための方法および組成物
EP4051241A4 (de) 2019-10-28 2023-12-06 Abraxis BioScience, LLC Pharmazeutische zusammensetzungen aus albumin und rapamycin
TW202200135A (zh) * 2020-05-08 2022-01-01 國立大學法人熊本大學 一種新穎血管疾病治療劑
US20230414590A1 (en) * 2020-11-12 2023-12-28 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Therapeutic small molecules for treatment of pulmonary hypertension
WO2024025991A1 (en) * 2022-07-27 2024-02-01 The Methodist Hospital System Methods for diagnosis and treatment of pulmonary hypertension
WO2024081674A1 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5439686A (en) 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
WO1998014174A1 (en) 1996-10-01 1998-04-09 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
WO1999000113A1 (en) 1997-06-27 1999-01-07 Vivorx Pharmaceuticals, Inc. Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US6096331A (en) 1993-02-22 2000-08-01 Vivorx Pharmaceuticals, Inc. Methods and compositions useful for administration of chemotherapeutic agents
US6537579B1 (en) 1993-02-22 2003-03-25 American Bioscience, Inc. Compositions and methods for administration of pharmacologically active compounds
US6749868B1 (en) 1993-02-22 2004-06-15 American Bioscience, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US20050004002A1 (en) 2002-12-09 2005-01-06 American Bioscience, Inc. Compositions and methods of delivery of pharmacological agents
US20050152979A1 (en) 2003-09-05 2005-07-14 Cell Therapeutics, Inc. Hydrophobic drug compositions containing reconstitution enhancer
WO2006089207A2 (en) 2005-02-18 2006-08-24 Abraxis Bioscience, Inc. Drugs with improved hydrophobicity for incorporation in medical devices
US20060263434A1 (en) 2005-02-18 2006-11-23 Desai Neil P Combinations and modes of administration of therapeutic agents and combination therapy
WO2007027941A2 (en) 2005-08-31 2007-03-08 Abraxis Bioscience, Llc. Compositions and methods for preparation of poorly water soluble drugs with increased stability
WO2007027819A2 (en) 2005-08-31 2007-03-08 Abraxis Bioscience, Llc. Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5540931A (en) * 1989-03-03 1996-07-30 Charles W. Hewitt Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants
US20070117862A1 (en) * 1993-02-22 2007-05-24 Desai Neil P Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US6753006B1 (en) * 1993-02-22 2004-06-22 American Bioscience, Inc. Paclitaxel-containing formulations
US5650156A (en) * 1993-02-22 1997-07-22 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of nutriceuticals and compositions useful therefor
US5362478A (en) * 1993-03-26 1994-11-08 Vivorx Pharmaceuticals, Inc. Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell
CA2155947C (en) * 1993-02-22 2007-08-21 Mark W. Grinstaff Methods for in vivo delivery of biologics and compositions useful therefor
US5665382A (en) * 1993-02-22 1997-09-09 Vivorx Pharmaceuticals, Inc. Methods for the preparation of pharmaceutically active agents for in vivo delivery
US6528067B1 (en) * 1993-02-22 2003-03-04 American Bioscience, Inc. Total nutrient admixtures as stable multicomponent liquids or dry powders and methods for the preparation thereof
US5665383A (en) * 1993-02-22 1997-09-09 Vivorx Pharmaceuticals, Inc. Methods for the preparation of immunostimulating agents for in vivo delivery
US5997904A (en) * 1993-02-22 1999-12-07 American Bioscience, Inc. Total nutrient admixtures as stable multicomponent liquids or dry powders and methods for the preparation thereof
US8137684B2 (en) * 1996-10-01 2012-03-20 Abraxis Bioscience, Llc Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US8853260B2 (en) * 1997-06-27 2014-10-07 Abraxis Bioscience, Llc Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20030199425A1 (en) * 1997-06-27 2003-10-23 Desai Neil P. Compositions and methods for treatment of hyperplasia
ITMI20001107A1 (it) * 2000-05-18 2001-11-18 Acs Dobfar Spa Metodo per il trattamento di tumori solici mediante microparticelle di albumina incorporanti paclitaxel
US20030054042A1 (en) * 2001-09-14 2003-03-20 Elaine Liversidge Stabilization of chemical compounds using nanoparticulate formulations
EP1494699A4 (de) * 2002-04-11 2009-07-22 Childrens Medical Center Verfahren zur hemmung der vaskulären hyperpermeabilität
WO2004060283A2 (en) * 2002-12-16 2004-07-22 Nitromed, Inc. Nitrosated and nitrosylated rapamycin compounds, compositions and methods of use
US20050119330A1 (en) * 2003-03-17 2005-06-02 Kao Peter N. Use of antiproliferative agents in the treatment and prevention of pulmonary proliferative vascular diseases
US20050038498A1 (en) * 2003-04-17 2005-02-17 Nanosys, Inc. Medical device applications of nanostructured surfaces
DE10347994A1 (de) * 2003-10-15 2005-06-16 Pari GmbH Spezialisten für effektive Inhalation Wässrige Aerosol-Zubereitung
CA2561717A1 (en) * 2004-05-17 2005-11-24 Novartis Ag Combination of organic compounds
WO2006053754A1 (en) * 2004-11-19 2006-05-26 Novartis Ag COMBINATIONS OF ANTI-ATHEROSCLEROTIC PEPTIDES AND AN mTOR INHIBITING AGENT AND THEIR METHODS OF USE
US8735394B2 (en) * 2005-02-18 2014-05-27 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
US20070166388A1 (en) * 2005-02-18 2007-07-19 Desai Neil P Combinations and modes of administration of therapeutic agents and combination therapy
EA200701998A1 (ru) * 2005-03-17 2008-02-28 Элан Фарма Интернэшнл Лтд. Композиции для инъекций наночастиц иммунодепрессивных соединений
WO2006113579A2 (en) * 2005-04-16 2006-10-26 Michigan State University Tumor inhibition by modulating sprouty expression or activity
KR20080007607A (ko) * 2005-05-16 2008-01-22 노파르티스 아게 심혈관 질환의 치료 및/또는 예방을 위한 라파마이신유도체의 용도
US20080280987A1 (en) * 2006-08-31 2008-11-13 Desai Neil P Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases
US20100112077A1 (en) * 2006-11-06 2010-05-06 Abraxis Bioscience, Llc Nanoparticles of paclitaxel and albumin in combination with bevacizumab against cancer
ES2700074T3 (es) * 2006-12-14 2019-02-13 Abraxis Bioscience Llc Terapia para el cáncer de mama sobre la base del estado de los receptores hormonales con nanopartículas que comprenden taxano
US7855024B2 (en) * 2006-12-27 2010-12-21 Proton Energy Systems, Inc. Compartmentalized storage tank for electrochemical cell system
NZ621972A (en) * 2007-03-07 2015-09-25 Abraxis Bioscience Llc Nanoparticle comprising rapamycin and albumin as anticancer agent
PL2155188T3 (pl) * 2007-06-01 2014-03-31 Abraxis Bioscience Llc Sposoby i kompozycje do leczenia nawrotowego raka
MX2010011165A (es) * 2008-04-10 2011-02-22 Abraxis Bioscience Llc Composiciones de derivados de taxano hidrofobos y sus usos.
ES2668837T3 (es) * 2008-12-11 2018-05-22 Abraxis Bioscience, Llc Terapia de combinación que incluye un taxano y un agente terapéutico adicional
CA2758913A1 (en) * 2009-04-15 2010-10-21 Abraxis Bioscience, Llc Prion free nanoparticle compositions and methods of making thereof
US9775819B2 (en) * 2009-09-16 2017-10-03 R.P. Scherer Technologies, Llc Oral solid dosage form containing nanoparticles and process of formulating the same using fish gelatin
ES2925531T3 (es) * 2010-03-29 2022-10-18 Abraxis Bioscience Llc Procedimientos para mejorar la administración de fármacos y la eficacia de agentes terapéuticos
US8183104B2 (en) * 2010-07-07 2012-05-22 Hobbs Christopher C Method for dual-channel nanowire FET device

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6537579B1 (en) 1993-02-22 2003-03-25 American Bioscience, Inc. Compositions and methods for administration of pharmacologically active compounds
US5439686A (en) 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US6749868B1 (en) 1993-02-22 2004-06-15 American Bioscience, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5916596A (en) 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US6096331A (en) 1993-02-22 2000-08-01 Vivorx Pharmaceuticals, Inc. Methods and compositions useful for administration of chemotherapeutic agents
US6506405B1 (en) 1993-02-22 2003-01-14 American Bioscience, Inc. Methods and formulations of cremophor-free taxanes
WO1998014174A1 (en) 1996-10-01 1998-04-09 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
WO1999000113A1 (en) 1997-06-27 1999-01-07 Vivorx Pharmaceuticals, Inc. Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20050004002A1 (en) 2002-12-09 2005-01-06 American Bioscience, Inc. Compositions and methods of delivery of pharmacological agents
US20050152979A1 (en) 2003-09-05 2005-07-14 Cell Therapeutics, Inc. Hydrophobic drug compositions containing reconstitution enhancer
WO2006089207A2 (en) 2005-02-18 2006-08-24 Abraxis Bioscience, Inc. Drugs with improved hydrophobicity for incorporation in medical devices
US20060263434A1 (en) 2005-02-18 2006-11-23 Desai Neil P Combinations and modes of administration of therapeutic agents and combination therapy
WO2007027941A2 (en) 2005-08-31 2007-03-08 Abraxis Bioscience, Llc. Compositions and methods for preparation of poorly water soluble drugs with increased stability
WO2007027819A2 (en) 2005-08-31 2007-03-08 Abraxis Bioscience, Llc. Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ADNOT ET AL., J. CLIN. INVEST., vol. 87, 1999, pages 155 - 162
CARTER ET AL., ADV. PROTEIN. CHEM., vol. 45, 1994, pages 153 - 203
CURRY ET AL., NAT. STRUCT. BIOL., vol. 5, 1998, pages 827 - 835
FEHSKE ET AL., BIOCHEM. PHARMCOL., vol. 30, 1981, pages 687 - 692
GOODMAN ET AL.: "The Pharmacological Basis of Therapeutics", 1996, MCGRAW-HILL
HE ET AL., NATURE, vol. 358, 1992, pages 209 - 215
KRAGH-HANSEN, DAN. MED. BULL., vol. 1441, 1990, pages 131 - 140
SUGIO ET AL., PROTEIN. ENG., vol. 12, 1999, pages 439 - 446
VORUM, DAN. MED. BULL., vol. 46, 1999, pages 379 - 399
ZAIMAN ET AL., AM. J. RESPIR. CELL MOL. BIOL., vol. 33, 2005, pages 425 - 431

Also Published As

Publication number Publication date
WO2008137148A2 (en) 2008-11-13
US20140271871A1 (en) 2014-09-18
HK1255083A1 (zh) 2019-08-02
CA2686736A1 (en) 2008-11-13
US20180133157A1 (en) 2018-05-17
EP3326630A3 (de) 2018-08-29
US20100166869A1 (en) 2010-07-01
WO2008137148A3 (en) 2009-02-19
EP2146707A2 (de) 2010-01-27
US20210315823A1 (en) 2021-10-14

Similar Documents

Publication Publication Date Title
US20210315823A1 (en) Methods and compositions for treating pulmonary hypertension
AU2017225031B2 (en) Intravascular delivery of nanoparticle compositions and uses thereof
US8927019B2 (en) Methods and compositions for treating recurrent cancer
EP1585548B1 (de) Zusammensetzungen, pharmakologisch wirksame agenzien enthaltend und wirkstofffreigabemethoden
RU2433818C2 (ru) Композиции, включающие слаборастворимые в воде фармацевтические вещества и противомикробные вещества
US20210085621A1 (en) Methods and compositions for treating pulmonary hypertension
KR20120068035A (ko) 약리학적 물질의 조성물 및 그 전달방법
EP1337249A1 (de) Zusammensetzungen und verfahren zur verabreichung von pharmakologisch aktiven verbindungen
KR20050104383A (ko) 폐 고혈압의 치료를 위한 에스트라디올 대사물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED

AC Divisional application: reference to earlier application

Ref document number: 2146707

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/337 20060101ALI20180725BHEP

Ipc: A61K 31/436 20060101AFI20180725BHEP

Ipc: A61P 9/14 20060101ALI20180725BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20190228

RBV Designated contracting states (corrected)

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1255083

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20200420

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20230216